Chlamydial Pathogeneis in the Reproductive Tract

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The objective of this project (2) is to characterize essential correlates of chlamydial infection of the human reproducfive tract jn the human reproductive tract. This will prime effective translational research through the identificafion and characterizafion of chlamydial anfigens of relevance to vaccine development and of physiologic or pathogenefic mechanisms that are at play in the complex, natural environment of the female genital tract and provide targets for possible chemotherapeutic intervenfion. The project involves extensive collaboration with the complementary projects 1 and 3 of the CRC and will rely on Cores B, C and D for the provision of guinea pig and human sera and swabs, and biostafistical analysis of the results, respectively. In a first phase, the virulence of C. trachomatis and C. cawae genital isolates will be quantified in relafionship to genome sequence type and reproductive tract ecology using a pafient cohort representative of genital chlamydial disease in humans. Virulence will be measured using genomic doubling, infecfious yield, inclusion fusogenicity and pathology as measurable physiological/pathogenic traits or endpoints, and using biomathemafical modeling of Intracellular development and correlated pathology. A second phase of the research will be to investigate in relationship to genome sequence type and reproducfive tract ecology the funcfional diversity of two gene families of C. trachomatis and C. caviae encoding inclusion membrane proteins (Inc) and effector proteins of the virulence-associated type III secretion (T3S) system that are targets for possible chemotherapeutic intervention. The developmental expression of selected inc and T3S effector genes in variants of C. trachomatis and C. cawae will be characterized and subcellular and molecular targets of variant Inc and T3S effector proteins will be identified. Finally, the diversity of the vaccine target pmp gene family and Pmp-specific antibody responses in C. /rac/7omaf/s-infected patients and C. cawae-infected guinea pigs will be investigated in relationship to genome sequence type and reproducfive tract ecology. This will be achieved through characterization of the developmental expression of pmp genes in variants of C. trachomatis and C. cawae, profiling the high frequency on/off switching of Pmp expression in selected variants and performing cross-sectional and longitudinal invesfigafions of the Pmp-specific anfibody response comparatively in infected humans and guinea pigs.